Manufacture of aromatic arsenic compounds containing an isoxazine ring



Patented July 22, 1930 .u1virE:o STATES PATENT orrlcr.

'GEORGEV'NEWBERY, 0F SURREY, ENGLAND, assrenon T0 MAY & BAKERLIMITED, 0F onnomnnemtnn, A :snrrrsn COMPANY v MANUFACTURE on AROMATIC aitsnmc COMPOUNDS CONTAINING AN IsoxAzINE RING No Drawing. Application filed ll'une 27, 1927, Serial No."201,970, and in GreatBritain as s, 1926.

The present invention is for the manufacture of aromatic compounds of arsenic comprising an isoxazin'e ring, that is, compounds containing arsenic directly linked to a car- 5 bon atom of an aryl nucleus in an arylisoxazine ring system.

The invention has particular reference to the manufacture of arsenic derivatives of the lit-benzisoxazine ring {and comprises the 10 manufacture ofbenzisoxazine arsinic acids,

and arsenobisfbenzisoxazme compounds. 1 According to the present invention, aromatic compounds of arsenic comprising an isoxazine ring are manufactured by reducing 5 an o-nitro-aryloxy-acetic acid arsenic derivative, that is such a derivative wherein there is a nitro and an oxyacetic'acid group in adj acent positions in the aryl nucleus, for example, o-nitro-phenoXyace.t-ic acid arsi nic acid. Depending on the conditions of the reduc tion, suchast'emperature and concentration of the reagents, and particularly on the reducing agent selected, the reduction may be effected so as to obtain asdesired either an arylison-azine arsenic compound, or an arseno-bis arylisoXazine derivative."

It follows that since the last type of product is in a lower state of oxidation than the second, and the second in turn in a lower state of oxidation than the 1 initial compound, the

second compound may be preparedtrom the first, and the third either from the first or the :second-, by appropriate adjustment of the reductizon conditions; and hence the reaction may be .efiected in separate stages, with .isolation' ofrthe first-formed product, or may be carried through from the beginning as an integral one-stage process to the formation of the arseno compound.

For example, when o-nitrophenoxy'acetic acid arsinic acid is ,reducedwith a suitable mild reducing agent, such, for example, .as

ferrous hydroxide or glucose in an alkaline.

medium, instead of the Q-ami-no-phenoxyacetic acid arsinic acid which might be ex pected, there .is produced, by elimination of a molecule of water, a 3-hydroXy-1;L-benzisoxazine'arsinic acid. On the other hand, if a ,more powerful reducing agent, such as to sodium hydrosul phite or hypophosphorous the acid be used, there may be directly obtained corresponding arsenobis-(8-hydroxylzt-benzisoxazine). In further alternative, 7 this latter compound may alsobe obtained from the 3-hydroXy-1zt-benzisoxazine arsinic' acid after separation and appropriate purification asmay prove desirable.

Thus, in particular, there are obtained from Q-nitro-phenoxyacetic acid 4t-arsinic I 7 acid (Christiansen:J.A. O. 5.44; 1922. 2239) by reduction with (a) ferrous hydroxide or glucose in an alkaline medium, 3-hydroxy 1:t-benzisoxazina6-arsinic acid; and by reduction with (1)) sodium hydrosulphite,

6 6 arseno bis-(8-hydroXy-1z t-benzisoxazine). This lattercompound is also obtainable directly from the Q-nitro-phenoxyactic acid-tarsinic acid by reduction withsodium. hydrosulphite. Both the intermediate and the final benisoxazine derivatives possess val- .uable therapeutic properties for the treatment of trypanosomiasis and like parasitic diseases.

It is to be appreciated that the o-nitroarylonyacetic acid arsenic compounds may be further substituted in the nucleus, and also that the term embraces equivalent compounds derived from acetic acid substituted in the a position and their reducible equivalents, such] as the esters or the amide. Hence, 2- 1 alkylor Q-aryl-isoxazines or -isoxazones may be prepared according to the invention. The following are example of waysin which the invention may be carried into 'effeet, but it will be appreciated that these examples are given for illustrative purposes and that the invention is not limited thereby.

Example 1 ferrous sulphate with 700 cc. of water and a solution of 280 grams of caustic soda in 400 cc. of water. To this paste, cooled to about 30 to (1, are added 130 grams of G-acetylamino-2-nitro-phenoxyacetic acid-4- arsenic acid dissolved in 700 cc. of atwicenormal solution of sodium carbonate. After removal of ferric hydroxide and acidification of the reaction mixture as in Example I, there .is obtained a crystalline substance, which has been proved to be S-acetylamino- '8-hydroxy-1 a benaisoxazine-6rarsinic acid,

2 b0 Q to oH ,oAS Nod nor! u,

' I. OH H E H 011i 2-nitrophenoxyacetic acid- 1 i 4-arsinic acid a product soluble in alkali carbonates and hy- 7 2 droxides but msoluble 1n acids, and yieldmg i6 3 a neutral sodium salt whose solution is su t- 3-hydroxy-1:4-beuzisoxazine G-arsinic acid 1 Example [I 27 grams of 3-hydroxy-1:l-benzisoxazine- G-arsinic acid are prepared according to the preceding example, and then dissolved in 200 cc. of water with the aid of cc. of a twicenormal solution of sodium carbonate, and the solution of the acid so obtained is added to a cooled solution in 2 litres of water of 30 gramsof magnesium chloride hexahydrate and. 100 grams of sodium hydrosulphite. The mixture is rapidly filtered, and the fil-' trate is warmed for one to two hours at a temperature of C. The light yellow product which separates is filtered off, washed and dried, and has been proved to be 6-6-arseno-bis- (3 hydroxy 1 a-benzisoxa zine). It is a product insoluble in alkalies and in acids. i

The reaction may be represented by the following structural formulae:

B-hydroxy-i:4-benzisoxazine- .G-arsinic acid 6z6-Arseno-bis-(3-hydroxy-1:4-benzisoxazine) E aample I I I An alkaline ferrous hydroxide paste is prepared by mixing 700 grams of crystallized able for administration by injection.

The 6-acetylamino-2-nitro-phenoxyacetic acid-t-arsinic acid may be conveniently prepared by the action of chloracetic acid on 3- nitro 4 hydroxy 5 acetylamino phenylarsinic acid, with appropriate removal of the liberated hydrochloric acid under such conditions as to prevent the reaction becoming either so acid or alkaline as to result in hydrolysis of the reaction product. Such conditions may be realized by the addition of sodium bicarbonate as an acid reaction develops;

The 3 nitro -4c-hydroxy 5 acetylaminophenylarsinic acid may in its turn be obtained by the nitration of 3-acetylamino-4zhydroxyphenylarsinic acid under the usual conditions. f

Example IV 33 grams of 8-acetylamino-8-hydroxy- 1:4-benzisoxazine-6-arsinic acid are first prepared from 6-acetyl amino, Q-nitro-phenoxy acetic acid 4-arsinic acid by reduction with ferrous hydroxide paste as hereinbefore proved to be 6-6-arseno-bis-(S-acetylamino- 3-hydroxy-1': a-benzisoxazine) I claim 1. Process of manufacture of aromatic compounds of arsenic containing an isoxazine ring, 1 which comprises reducing an arylarsenic compound containing a nitro-' and an oxyacetic acid-group in adjacent positions in the aryl nucleous under mild conditions of reduction to result in the nitrogroup only of the initial compound being attacked with the formation of the isoXazine ring and reducing the resulting isoxazine derivative under energetic conditions to give the corresponding arseno-bis-arylisoxazine.

4:. Process of manufacture of aromatic compounds of arsenic containing an isoxazine ring, which comprises reducing an arylarsenic compound containing in adjacent positions in the aryl nucleus, a nitro-group and an oxyacetic acid-group derived from an cesulostituted acetic acid. V

5. Process 'of manufacture of aromatic compounds of arsenic containing an isoXazine ring, which comprises reducing an arylarsenic compound containing in adjacent positions in the aryl nucleus, a nitro-group and an oxyacetic acid-group derived from an ocsulostituted acetic acid, the conditions of reduction being such as to result in the formation of an arylisoxazine arsenic derivative.

In testimony whereof I aflix my signature.

GEORGE NEWBERY. 

